Project Summary Abstract Candidate: Ross Okimoto, MD is a medical oncologist who believes that disease focused basic science research can improve outcomes for patients with cancer. Dr. Okimoto's long-term goal is to lead an independent laboratory-based translational research program aimed at identifying and targeting the molecular underpinnings of cancer metastasis. With two recent first author publications in Nature Genetics and PNAS, Dr. Okimoto has demonstrated potential as a translational cancer researcher. This K08 application will be critical for his ongoing career development, providing him with key mentorship and training in 1) oncogene mediated transcriptional regulation of normal and malignant progression; 2) advanced microscopy techniques; and 3) employing disease specific preclinical tools to enhance therapeutic modeling and enable clinical translation. Research: Metastasis accounts for >90% of cancer related death, yet the ability to inhibit the spread of cancer is hindered by the lack of pro-metastatic targets and robust preclinical models that recapitulate human disease. Through development of an in vivo orthotoptic lung cancer metastasis model, Dr. Okimoto recently found that the transcriptional repressor, Capicua (CIC), suppresses lung cancer metastasis. Since the candidate found that CIC expression is decreased upon ERK activation, he hypothesizes that ERK inhibition can restore CIC expression to block metastasis. The following specific aims are proposed: 1) to test if CIC is a direct physical and functional substrate of ERK signaling; 2) to test if MEK-ERK inhibition restores CIC expression to inhibit metastasis in a well-defined orthotopic mouse model. Mentorship and Training: Dr. Okimoto's training will be accomplished through formal coursework and under direct mentorship of world leaders including Trever Bivona, MD, PhD, a thoracic oncologist with expertise in molecular targeted therapies. Dr. Bivona has extensive research support from the NIH (3 NCI-funded R01's and the DP2 Directors New Innovator's Award), and has mentored five fellows to independence within the past five years. Dr. Okimoto will be co-mentored by Zena Werb, PhD, an expert in transcriptional metastatic regulation. Dr. Werb was the recipient of the UCSF Lifetime Achievement in Mentoring Award in 2015, recognizing her devotion to mentoring young physician- scientist to independence. In addition to his mentorship committee, Dr. Okimoto has assembled a word class team of physician-scientist advisors including, Kevin Shannon, MD (expert in mouse models and MAPK signaling), Andrei Goga, MD, PhD (oncogenic transcriptional control), and Neil Shah, MD, PhD (preclinical/clinical therapeutics) to provide guidance and to ensure he succeeds in transitioning into an independent physician-scientist. Environment: The candidate's training and research will be performed at the University of California, San Francisco, a world-renowned center of excellence in translational medicine and research. Dr. Okimoto will be provided with all the institutional resources necessary to complete the proposed experiments in a well-integrated community of physicians and scientists. Successful completion of the proposed research will provide preclinical rationale to use clinically approved MEK-ERK inhibitors to block lung cancer metastasis in a patient population with few therapeutic options.